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p53 mutant mice that display early ageing-associated phenotypes

Abstract

The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.

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Figure 1: Structure and expression of the mutant p53 m allele.
Figure 2: Longevity in p53+/+, p53+/-, p53+/m, p53-/- and p53-/m mice.
Figure 3: Transformation and p53 response phenotypes.
Figure 4: Phenotypes of aged p53+/+ and p53+/m mice.
Figure 5: Bone phenotypes in p53+/+ and p53+/m mice.
Figure 6: Skin and hair growth phenotypes in p53+/+ and p53+/m mice.
Figure 7: Stress responses in p53+/+ and p53+/m mice.
Figure 8: Ageing-related phenotypes observed in pL53 transgenic mice.

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Acknowledgements

We thank X.-J. Wang, G. Van Zant, D. Roop, R. Waikel, P. Biggs, M. Patel, S. Wojcik, R. Levasseur, V. Hortenstine, R. Ford, S. Wojcik, C. Pickering, R. Geske and M. Oren for advice and technical assistance. We also thank G. Lozano for luciferase and p53 plasmids. This study was supported by the National Cancer Institute.

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Correspondence to Lawrence A. Donehower.

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Tyner, S., Venkatachalam, S., Choi, J. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002). https://doi.org/10.1038/415045a

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